Breast Cancer Research and Treatment

, Volume 165, Issue 1, pp 41–51 | Cite as

Combination breast cancer chemotherapy with doxorubicin and cyclophosphamide damages bone and bone marrow in a female rat model

  • Chiaming Fan
  • Kristen R. Georgiou
  • Howard A. Morris
  • Ross A. McKinnon
  • Dorothy M. K. Keefe
  • Peter R. Howe
  • Cory J. Xian
Preclinical study



Anthracyclines (including doxorubicin) are still the backbone of commonly used breast cancer chemotherapy regimens. Despite increasing use of doxorubicin and cyclophosphamide (AC) combinations for treating breast cancer, their potential to cause adverse skeletal effects remains unclear.


This study examined the effects of treatments with the AC regimen on bone and bone marrow in adult female rats.


AC treatment for four cycles (weekly intravenous injection of 2 mg/kg doxorubicin and 20 mg/kg cyclophosphamide) resulted in a reduced volume of trabecular bone at the metaphysis, which was associated with reduced serum levels of 25-hydroxy vitamin D3 and alkaline phosphatase. Reductions in densities of osteocytes and bone lining cells were also observed. In addition, bone marrow was severely damaged, including a severe reduction in bone marrow cellularity and an increase in marrow adipocyte content. Accompanying these changes, there were increases in mRNA expression of adipogenesis regulatory genes (PPARγ and FABP4) and an inflammatory cytokine (TNFα) in metaphysis bone and bone marrow.


This study indicates that AC chemotherapy may induce some bone loss, due to reduced bone formation, and bone marrow damage, due to increased marrow adiposity. Preventive strategies for preserving the bone and bone marrow microenvironment during anthracycline chemotherapy warrant further investigation.


Breast cancer chemotherapy Bone loss Bone marrow adiposity Bone marrow damage Bone turnover Osteoclasts 



This work was funded in parts by project grants from the Australian National Health Medical Research Council (NHMRC) (1010752) and Australian Research Council (LP120100519). Cory J. Xian is funded by NHMRC Senior Research Fellowship (1042105).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Chiaming Fan
    • 1
  • Kristen R. Georgiou
    • 1
  • Howard A. Morris
    • 1
  • Ross A. McKinnon
    • 1
    • 2
  • Dorothy M. K. Keefe
    • 1
    • 3
    • 4
  • Peter R. Howe
    • 5
  • Cory J. Xian
    • 1
  1. 1.School of Pharmacy and Medical Sciences, and Sansom Institute for Health ResearchUniversity of South AustraliaAdelaideAustralia
  2. 2.Flinders Centre for Innovation in Cancer, School of MedicineFlinders UniversityAdelaideAustralia
  3. 3.SA Cancer ServiceSA Cancer Clinical NetworkAdelaideAustralia
  4. 4.Centre of Cancer MedicineUniversity of AdelaideAdelaideAustralia
  5. 5.Clinical Nutrition Research Centre, School of Biomedical Sciences and PharmacyUniversity of NewcastleCallaghanAustralia

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